Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells

Zhang, Caixia; Yeh, Shuyuan; Chen, Yen Ta; Wu, Cheng‐Chia; Chuang, Kuang Hsiang; Lin, Hung Yun; Wang, Ruey Sheng; Chang, Yu Jia; Mendis-Handagama, Chamindrani; Hu, Li-Quan; Lardy, Henry A.; Chang, Chawnshang

doi:10.1073/pnas.0608556103

Cited by 134 publications

(111 citation statements)

References 43 publications

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“…Gene expression studies suggest that also other Sertoli cell activities such as expression of transferrin mRNA may depend at least in part on such an indirect pathway [103]. The contention that peritubular myoid cells may modulate or even mediate some effects of androgens on Sertoli cells and spermatogenesis is supported not only by in vitro data mentioned earlier [75,76,78,90,115] but also by the recent demonstration that animals with a knockout of the AR in peritubular cells display a reduction in testis size and oligozoöspermia [116]. Some caution may be needed in the interpretation of the data on this peritubular AR knockout, however, since the construct used to target Cre expression to peritubular myoid cells has also been shown to induce Cre expression in other cells such as vascular smooth muscle cells [117].…”

Section: Lessons From Sertoli Cell-selective Knockout Modelssupporting

confidence: 61%

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Verhoeven¹,

Denolet²,

Swinnen³

et al. 2008

IEMAMC

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Androgens play a key role in the control of spermatogenesis and interference with their intratesticular secretion and action is a critical element in many contraceptive strategies. Nonetheless, the cellular and molecular mechanisms by which androgens control germ cell development remain poorly understood. Recent transgenic models in which the androgen receptor (AR) is selectively ablated in Sertoli cells show unambiguously that the Sertoli cell is the main target for androgen action in the control of spermatogenesis. A number of additional mouse models have been developed mimicking human diseases in which mutations of the AR cause disturbed fertility without affecting male development. Transcriptional profiling studies in mice with Sertoli cell-selective AR ablation and in some other experimental paradigms have tried to identify androgen-regulated genes relevant to the control of spermatogenesis. The overlap in genes identified in different studies is poor but this may be due mainly to dissimilarities in experimental setup. In all studies, relatively large numbers of genes rather than a few key genes seem to be affected by androgen action. Genes related to tubular restructuring, cell junction dynamics, cytoskeleton, solute transportation and vitamin A metabolism are prominently present. Although further work is obviously needed, it may be anticipated that these studies will result in the identification of subsets of genes that can be used as diagnostic tools as well as in the identification of targets for the development of novel contraceptives.

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Section: Lessons From Sertoli Cell-selective Knockout Modelssupporting

confidence: 61%

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Verhoeven¹,

Denolet²,

Swinnen³

et al. 2008

IEMAMC

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“…During embryonic gonadal development, peritubular myoid cells differentiate from cells that migrate from neighboring mesonephros, which is essential for normal testicular cord formation (Tilmann & Capel 1999). During postnatal life, peritubular myoid cells provide normal tubule morphology and contractility, processes that are critical for spermatogenesis (Zhang et al 2006). Peritubular myoid cells and Sertoli cells interact with each other through growth factor-mediated feedback; these cells collaborate to produce extracellular matrix components which comprise the basement membrane that separates these two cell types (Skinner et al 1985, Skinner 1991.…”

Section: Testicular Cells Include Germ Cells As Well As Leydig and Smentioning

confidence: 99%

The hepatocyte growth factor system as a regulator of female and male gonadal function

Zachow

Uzumcu²

2007

Journal of Endocrinology

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The hepatocyte growth factor (HGF) system comprises HGF, its receptor (the c-met tyrosine kinase), HGF activator (HGFA) protein, and HGFA inhibitor (HAI). The components of the HGF system have been identified in a plethora of tissues to include the ovary and testis. In its traditional context, the HGF system works via paracrine-and autocrine-mediated feedback in which HGF (of mesenchymal origin) binds and activates c-met (within epithelial cells); target cells then respond to HGF via any number of morphogenic and functional changes. The concomitant presence of HGFA and HAI suggests that HGF bioactivity can be locally modulated. A number of studies have collectively shown that the mammalian ovary and testis contain HGF, c-met, and HGFA; very little is currently known regarding HAI within the gonad. Within the ovary, HGF controls numerous key functions which collectively regulate the growth and differentiation of ovarian follicles; these include cell growth, steroidogenesis, and apoptosis within theca cells and/or granulosa cells. Comparatively, less is known about the function of HGF within the testicular Leydig and Sertoli cells, but evidence is emerging that HGF may regulate somatic cell function, including Leydig cell steroidogenesis. Changes in the cellular origin of HGF and c-met during fetal and postnatal testicular development suggest that HGF, in collaboration with other growth factors, may regulate important aspects of testicular cell morphogenesis and differentiation which enable male sexual viability. Likewise, experimental evidence showing that HGF can modulate many vital processes which enable ovarian follicle growth, differentiation, and function indicate the importance of HGF in female reproduction. This review presents what is currently known regarding the expression of the HGF system and its function within the ovary and testis.

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“…Oxygen Species-A monocellular suspension of testicular cells was prepared as described previously (32). Briefly, the tunica albuginea was removed, and the seminiferous tubules were minced in PBS to release the testicular cells.…”

Section: Flow Cytometry Analysis Of Testicular Cells For Dna Content mentioning

confidence: 99%

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

Imai

Hakkaku

Iwamoto

et al. 2009

Journal of Biological Chemistry

176

141

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Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an intracellular antioxidant enzyme that directly reduces peroxidized phospholipids. GPx4 is strongly expressed in the mitochondria of testis and spermatozoa. We previously found a significant decrease in the expression of GPx4 in spermatozoa from 30% of infertile human males diagnosed with oligoasthenozoospermia (Imai, H., Suzuki, K., Ishizaka, K., Ichinose, S., Oshima, H., Okayasu, I., Emoto, K., Umeda, M., and Nakagawa, Y. (2001) Biol. Reprod. 64, 674 -683). To clarify whether defective GPx4 in spermatocytes causes male infertility, we established spermatocyte-specific GPx4 knock-out mice using a CreloxP system. All the spermatocyte-specific GPx4 knock-out male mice were found to be infertile despite normal plug formation after mating and displayed a significant decrease in the number of spermatozoa. Isolated epididymal GPx4-null spermatozoa could not fertilize oocytes in vitro. These spermatozoa showed significant reductions of forward motility and the mitochondrial membrane potential. These impairments were accompanied by the structural abnormality, such as a hairpin-like flagella bend at the midpiece and swelling of mitochondria in the spermatozoa. These results demonstrate that the depletion of GPx4 in spermatocytes causes severe abnormalities in spermatozoa. This may be one of the causes of male infertility in mice and humans.A frequent cause of male infertility is defective sperm function, which is the main problem for close to a quarter of couples who attend infertility clinics (1-4). Considerable efforts are now focused on the identifying ultrastructural and/or molecular defects in the spermatozoa or seminal plasma to develop solutions to various types of male infertility.Phospholipid hydroperoxide glutathione peroxidase (GPx4) 2 is an intracellular selenoprotein that directly reduces peroxidized phospholipids produced in cell membranes (5). The GPx4 gene has a complex intron/exon structure (6, 7). Three different transcripts of GPx4 exist, differing in their 5Ј extension and coding for a cytosolic protein (non-mitochondrial GPx4), a mitochondrial protein (mitochondrial GPx4), and a nuclear protein (nucleolar GPx4), respectively (6, 7). After cleavage of the N-terminal mitochondrial import sequence of mitochondrial GPx4, the mature protein becomes identical to the 20-kDa non-mitochondrial GPx4 (8, 9). Nuclear GPx4 was recently identified as a sperm nucleus-specific 34-kDa selenoprotein (called snGPx, for sperm nucleus-specific glutathione peroxidase) (10). It is formed by use of an alternative promoter and start codon localized in the first intron of the GPx4 gene (7, 10, 11). We previously reported that 34-kDa GPx4 localized in nucleoli in several cell lines by using an N-terminal nucleolar import signal (11). We call hereafter nuclear GPx4 nucleolar GPx4, because non-mitochondrial 20-kDa GPx4 exists both in cytosol and in the nucleus (12). Expression of three types of GPx4 is induced significantly in testis during spermatogenesis, especiall...

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Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells

Abstract: Androgens and the androgen receptor (AR) play important roles in the testes. Previously we have shown that male total AR knockout (T-AR

Cited by 134 publications

References 43 publications

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

The hepatocyte growth factor system as a regulator of female and male gonadal function

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

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